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Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers.

Zhang Y, Qu X, Teng Y, Li Z, Xu L, Liu J, Ma Y, Fan Y, Li C, Liu S, Wang Z, Hu X, Zhang J, Liu Y - Oncotarget (2015)

Bottom Line: The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function.However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown.In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.

ABSTRACT
The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown. In the present study, we showed that c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy. Our findings identified a new regulatory mechanism of P-gp transport function in multiple drug-resistant gastric and breast cancers.

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Effect of Cbl-b on Dox therapeutic sensitivity of subcutaneous gastric cancer in mice(A) Effect of Cbl-b overexpression on tumor proliferation. SGC7901/Adr Control and SGC7901/Adr+Cbl-b were implanted subcutaneously into the right flanks of 4–6-week-old female nude mice (n = 5 mice per group), and tumor volume was measured on days 0, 8, 16, 24, 32 and 40 after implantation. (B) Cbl-b expression was analyzed in sections from subcutaneous SGC7901/Adr control and SGC7901/Adr+Cbl-b tumors by immunohistochemistry (× 20). (C–D) Average normalized tumor volume from mice (n = 5 per group) at the experimental end-point. Mean volumes and error bars representing 95% confidence intervals from three independent experiments are shown. *P = 0.34, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr+Cbl-b treated with PBS; *P = 0.12, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr Control treated with PBS; *P = 0.09, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr Control treated with Dox.
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Figure 5: Effect of Cbl-b on Dox therapeutic sensitivity of subcutaneous gastric cancer in mice(A) Effect of Cbl-b overexpression on tumor proliferation. SGC7901/Adr Control and SGC7901/Adr+Cbl-b were implanted subcutaneously into the right flanks of 4–6-week-old female nude mice (n = 5 mice per group), and tumor volume was measured on days 0, 8, 16, 24, 32 and 40 after implantation. (B) Cbl-b expression was analyzed in sections from subcutaneous SGC7901/Adr control and SGC7901/Adr+Cbl-b tumors by immunohistochemistry (× 20). (C–D) Average normalized tumor volume from mice (n = 5 per group) at the experimental end-point. Mean volumes and error bars representing 95% confidence intervals from three independent experiments are shown. *P = 0.34, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr+Cbl-b treated with PBS; *P = 0.12, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr Control treated with PBS; *P = 0.09, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr Control treated with Dox.

Mentions: The findings that Cbl-b could overcome Dox resistance in vitro were further explored by in vivo nude mice xenograft studies. Stable SGC7901/Adr cell lines overexpressing Cbl-b/pcDNA3.1 or pcDNA3.1 alone were subcutaneously implanted into the flanks of athymic nude mice. After tumors reached approximately 100 mm3 (7 days), the animals received intraperitoneal injection of either PBS or Dox (6 mg/kg) once per week. The results showed that in SGC7901/Adr+Cbl-b mice treated with Dox, tumor growth was significantly inhibited compared with that in the other three groups (Figure 5A–5D).


Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers.

Zhang Y, Qu X, Teng Y, Li Z, Xu L, Liu J, Ma Y, Fan Y, Li C, Liu S, Wang Z, Hu X, Zhang J, Liu Y - Oncotarget (2015)

Effect of Cbl-b on Dox therapeutic sensitivity of subcutaneous gastric cancer in mice(A) Effect of Cbl-b overexpression on tumor proliferation. SGC7901/Adr Control and SGC7901/Adr+Cbl-b were implanted subcutaneously into the right flanks of 4–6-week-old female nude mice (n = 5 mice per group), and tumor volume was measured on days 0, 8, 16, 24, 32 and 40 after implantation. (B) Cbl-b expression was analyzed in sections from subcutaneous SGC7901/Adr control and SGC7901/Adr+Cbl-b tumors by immunohistochemistry (× 20). (C–D) Average normalized tumor volume from mice (n = 5 per group) at the experimental end-point. Mean volumes and error bars representing 95% confidence intervals from three independent experiments are shown. *P = 0.34, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr+Cbl-b treated with PBS; *P = 0.12, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr Control treated with PBS; *P = 0.09, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr Control treated with Dox.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466646&req=5

Figure 5: Effect of Cbl-b on Dox therapeutic sensitivity of subcutaneous gastric cancer in mice(A) Effect of Cbl-b overexpression on tumor proliferation. SGC7901/Adr Control and SGC7901/Adr+Cbl-b were implanted subcutaneously into the right flanks of 4–6-week-old female nude mice (n = 5 mice per group), and tumor volume was measured on days 0, 8, 16, 24, 32 and 40 after implantation. (B) Cbl-b expression was analyzed in sections from subcutaneous SGC7901/Adr control and SGC7901/Adr+Cbl-b tumors by immunohistochemistry (× 20). (C–D) Average normalized tumor volume from mice (n = 5 per group) at the experimental end-point. Mean volumes and error bars representing 95% confidence intervals from three independent experiments are shown. *P = 0.34, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr+Cbl-b treated with PBS; *P = 0.12, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr Control treated with PBS; *P = 0.09, SGC7901/Adr+Cbl-b treated with Dox vs. SGC7901/Adr Control treated with Dox.
Mentions: The findings that Cbl-b could overcome Dox resistance in vitro were further explored by in vivo nude mice xenograft studies. Stable SGC7901/Adr cell lines overexpressing Cbl-b/pcDNA3.1 or pcDNA3.1 alone were subcutaneously implanted into the flanks of athymic nude mice. After tumors reached approximately 100 mm3 (7 days), the animals received intraperitoneal injection of either PBS or Dox (6 mg/kg) once per week. The results showed that in SGC7901/Adr+Cbl-b mice treated with Dox, tumor growth was significantly inhibited compared with that in the other three groups (Figure 5A–5D).

Bottom Line: The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function.However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown.In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, the First Hospital of China Medical University, Shenyang 110001, China.

ABSTRACT
The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown. In the present study, we showed that c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy. Our findings identified a new regulatory mechanism of P-gp transport function in multiple drug-resistant gastric and breast cancers.

Show MeSH
Related in: MedlinePlus